Exam 1: Genetics and Epigenetics in Cancer Flashcards
What are some examples of inherited or familial cancer syndromes?
- Hereditary breast and ovarian cancers: BRCA1 and BRCA2
- Li-Fraumeni syndrome: TP53 (inherited group of P53 mutations)
What percentage of cancers are estimated to involve acquired mutations by the American Cancer Society?
90-95%
(Commonly cell cycle or apoptosis regulators)
What are two factors associated with smoking that enhances de novo DNA methylation?
- Polycyclic aromatic hydrocarbons (PAH)
- Nicotine-derived nitrosamines (NDN)
How are DNA methylation enzymes directly influenced by PAH and NDN?
- DNA methylation regulation down-regulated (DNMT1; differentiation)
- DNA methyltransferase activation (DNMT3; de-differentiation)
What is CIMP?
CpG island methylator phenotype
What are some examples of DNMT3 activation that may be expressed?
- Carcinoembryonic antigen (CEA)
- Glypican-3
- alpha-fetoprotein (AFP)
Removal of methylation marks on developmental genes
DNA methylation dysregulation can cause methylation of normal tissue function genes, such as:
- p53 can be extensively methylated (codons 248, 273 are CpG rich exons)
- p53 expression may be lost
What happens to DNMT1 activity in many smoking-related cancers?
Down regulated
What mid stage genetic events are associated with an intermediate risk of developing oral cancer?
- 3p12: FHIT
- 9p21: p16
What happens to CpG methylation with DNMT3 dysregulation?
Increases (CIMP)
How are DNA repair enzymes affected by DNMT3 dysregulation?
Down regulated (methylated)
The frequency of replication errors affected by DNMT3 dysregulation is ____
Increased
If there is no loss of heterozygosity, there is a ____ risk of developing cancer
Low risk
How common is a 3p12; FHIT allelic imbalance (mutation) in HNSCC?
70-90%
3p12 loss is critical among the ____ events of progression
Earliest
What is p16?
Inhibitor of cyclin CDK
What is FHIT?
Fragile Histidine Triad gene (CpG methylated in 3p12 alteration)
What is the most commonly deleted/mutated DNA region in HNSCC?
9p21
What does p16 have?
- CpG-rich promoter region
- Exons 1 and 2 are also CpG rich
What does p16 inactivation lead to?
G1/S cell cycle progression
(associated with 9p21)
What are some of the high risk, late stage genetic events associated with additional loss of heterozygosity?
- 17p:p53
- 8p:p14/p19
What do 17p deletions or mutations involve?
p53 (tumor suppressor)
Who are p53 mutations 300% more likely in?
CpG exons in smokers than non-smokers
What do 8p deletions/mutations remove?
p14/p19
p14/p19 contain ____ in the promoter and exons
CpG-rich islands
____ transversions are more common in non-tobacco oral cancers
G to A transversions
Methylation and DNA mutations:
Where are G to T transversions common?
Methylated CpG sites
What does CIMP lead to?
- Site-specific mRNA downregulation
- DNA mutation (transversion)
What is the function of HOTAIR IncRNA overexpression?
Acts as a scaffold for histone demethylase
What are exosomes?
Microparticles 30-100 nm that contain miRNAs (found in all body fluids)
Which microRNA has intracellular and exosome positive control?
miR-16
____ is the most frequently upregulated microRNA in solid tumors, considered “onco-miR”
miR-21
____ has differential expression among cancers (promotes liver, lung, skin; inhibits bone, brain breast)
miR-365
Ras activation is associated with:
miR-21 that binds and turns off PTEN (tumor suppressor)
____ modulates pluripotency factors (NANOG) in stem cells and DNMT3 expression in cancers
miR-720
What two microRNAs are commonly expressed in oral cancers (OSCC)?
miR-21 and miR-365
miR-21 expression is reduced by:
Melatonin (MLT)
Where is miR-365 expressed?
Intracellularly
Where does differential exosome expression occur with miR-365?
Extracellularly
miR-720 is ____ expressed in oral cancer
Highly
What happens to DNMT3 in oral cancers?
Up-regulated
What is the correlation between miR-720 being highly expressed and DNMT3 being up-regulated in oral cancers?
R=0.8488 (strong correlation)
Chemotherapy resistant OSCC express:
miR-21
Which chemotherapy sensitive oral cancer miRNAs are expressed?
miR-145 and miR-155
What miRNA do chemotherapy resistant OSCCs express?
miR-375
What do chemotherapy resistant OSCCs not express?
miR-27
Chemotherapy sensitive OSCCs do not express:
miR-155
Chemotherapy sensitive OSCCs do express:
miR-145
miR-21 is considered:
“onco-miR,” mediates Cisplatin-resistance
miR-720
Modulates growth and DNMT3 expression in oral cancers
Genomic instability involves:
Hypomethylation of intergenic regions
What happens with illegitimate recombination between repeats (genomic instability)?
Translocations
What are the translocations in Burkitt’s lymphoma?
- t(8;14) (c-myc on chromosome 8)
- t(14;18) (Bcl-2 on chromosome 18)
What gene on chromosome 8 is associated with the t(8,14) translocation with Burkitt’s lymphoma?
c-myc
What type of translocation for Burkitt’s lymphoma is associated with Bcl-2?
t(14,18) translocation
What is lymphoma?
A blood cancer where lymphoma cells multiply and collect in your lymph nodes and other tissues. Over time, these cancerous cells impair your immune system
What is leukemia?
A type of cancer found in blood and bone marrow, caused by rapid production of abnormal white blood cells, which impairs the ability of bone marrow to produce red blood cells and platelets
Myeloid leukemia originates in ____ and myeloid precursor cells that give rise to ____
Myeloid cells (granulocytes); macrophages, neutrophils, and basophils
What is myeloma?
A blood cancer that specifically targets your plasma cells. Myeloma cells prevent the normal production of antibodies, leaving your body’s immune system weakened and susceptible to infection
What type of onset and progression does acute myeloid leukemia have?
Rapid onset and progression (fatal)
Where does AML typically develop?
Among monocyte or granulocyte precursors
Is AML more common in men or women?
Men (3:1)
Rate of therapy-related acute myeloid leukemia (AML) is ____
Rising
What are some symptoms of AML?
- Fatigue
- Bruising
- Pallor
What is an example of anti-cancer chemotherapy that can be used for AML?
Cisplatin
Oral symptom of AML
Gingival hypertrophy (swelling)
AML induced effects have ____ onset
Rapid (days or weeks)
How is an AML diagnosis made?
- Abnormal CBC (complete blood count)
- Abnormal blood smear
- Leukocytosis (excess of abnormal WBC)
- Auer rods
- Lack of granulocytosis
What percentage of oral and dental alterations are identified in AML patients?
More than 90%
What is one option for treatment of AML?
Anthracycline (topoisomerase inhibitor)
What happens in pediatric patients who take anthracycline?
- Impairs odontogenesis
- Microdontia in second premolars and second molars
What is the chromosomal translocation associated with chronic myeloid leukemia (CML)?
- Philadelphia chromosome
- t(9:22)
Is the fusion gene BCR-ABL on or off with chronic myeloid leukemia?
Always on –> cell divides uncontrollably
Most patients (men) diagnosed at CML ____ stage through ____
Chronic stage; elevated WBC
Blast phase of CML often includes:
Hepatosplenomegaly
What are some ways that CML can be diagnosed?
- Abnormal CBC (complete blood count)
- Granulocytosis excess of PMN
- Philadelphia chromosome t(9;22)
What is an oral symptom associated with CML thrombocytopenia?
Oral mucosal petechiae
What is the only curative treatment for CML?
Allogeneic stem cell transplant
Acute lymphoblastic leukemia (ALL) has ____ onset in _____
Rapid onset in children
Is the fusion gene BCR-ABL tyrosine kinase on or off with ALL?
Always on
Where does ALL develop?
Among immature lymphoblasts
What chromosome is involved with ALL?
Philadelphia chromosome reciprocal translocation t(9:22)
What is the most common cancer in children?
ALL
What are the risk factors for developing ALL?
- Exposure to ionizing radiation
- Li-Fraumeni syndrome
What are the oral symptoms associated with ALL?
- Fatigue, bruising, pallor
- Gingival hypertrophy (leukemic cell infiltration)
Regarding ALL, ____ onset is key
Rapid
How is ALL diagnosed?
- Abnormal CBC (complete blood count)
- Lymphocytosis (abnormal bone marrow biopsy)
What is the only curative treatment for ALL?
Allogeneic stem cell transplant
Chronic lymphocytic leukemia (CLL) develops among:
B-lymphocytes
What are the two types of CLL?
- IGVH mutated
- IGVH non-mutated
Does IGVH mutated CLL have a good or poor prognosis?
Poor, reduced treatment responsiveness
Is CLL usually symptomatic or asymptomatic?
Asymptomatic (found through abnormal WBC counts)
What is a less common symptom of CLL?
Enlarged lymph nodes
How are most CLL patients diagnosed?
- Through elevated lymphocytes > 15,000/mm^3
- Hypogammaglobulinemia without SCID
CLL has a ____ onset
Slow
What would be present in a peripheral blood smear of someone with CLL?
Smudge cells
What happens during MM development?
Immunoglobin heavy chain, oncogene translocation
What is chronic lymphocytic leukemia closely related to?
Multiple myeloma
What do MM abnormal plasma cells produce?
Abnormal antibodies
________ is strongly linked to MM
Obesity
What can MM lead to?
- Kyphosis
- Raindrop skull
Common symptoms of MM
Pain, numbness, swelling of the jaw
MM treatment
Bisphosphonates which inhibit bone resorption
What is the risk when taking bisphosphonates?
Medication-related osteonecrosis of the jaw (MRONJ)
In addition to the BCR-ABL fusion gene, what other fusion gene is present in ALL?
ETV6-RUNX fusion protein t(12;21)
